This invention relates to a quinolone synthetic antibacterial drug which is useful as a drug for human, animals, or fish, or as a antibacterial preservatives.
Since discovery of norfloxacin, antibacterial activity and pharmacokinetics of quinolone synthetic antibacterial drugs (including those containing pyridobenzoxazine skeleton) have been greatly improved, and, today, they are used in chemotherapy for infections including almost all systemic infections, and a large number of drugs are in clinical use.
However, a of bacteria exhibiting low sensitivity for quinolone synthetic antibacterial drugs have been recently increasing in its number in clinical field. For example, bacteria which are resistant to drugs other than quinolone synthetic antibacterial drugs, and which also exhibit low sensitivity to quinolone synthetic antibacterial drugs are increasing such as Gram positive coccus like Staphylococcus aureus (MRSA) and pneumococcus (PRSP) insensitive to β-lactam antibiotics and enterococcus (VRE) insensitive to aminoglycoside antibacterial drugs. Accordingly, there is a strong clinical demand for a drug exhibiting an improved effectiveness to Gram positive coccus.
In the meanwhile, antibacterial activity of recently developed quinolone synthetic antibacterial compounds are by far stronger than former quinolone synthetic antibacterial compounds. However, many such quinolone compound having high antibacterial activity have been reported to produce side effects based on physiological or pharmacological action not observed in the former quinolone synthetic antibacterial compounds. For example, restrictions are imposed on the administration of some compounds due to side effects such as development of abnormal blood glucose level, cardiotoxicity, or delayed allergy, or development of convulsion, and development and use as a drug have been abandoned in some compounds. In other words, many compounds have been found to be insufficient in their suitability as a drug due to the strong side effects despite their high antibacterial activity. Accordingly, a drug design methodology which is different from former compounds is required to thereby prevent the situation that a highly antibacterial compound can not be developed as a drug due to production of side effects. In other words, a design methodology is required that is capable of producing a compound which has a considerably high antibacterial activity comparable or similar to those of the conventional compounds, and at the same time, which is provided with suitability for a drug that allows use of the compound as a drug, for example, high safety without side effects.
Exemplary side effects which have been reported for the quinolone synthetic antibacterial agents include induction of convulsion associated with concomitant use of a nonsteroidal anti-inflammatory agent, central action (relatively light central nerve disorders such as reeling, headache, and insomnia as well as serious side effects such as development of lethal convulsion), phototoxicity (photosensitivity), hepatotoxicity, and cardiotoxicity (an abnormality observed as an abnormality of electrocardiogram which induces lethal arrhythmia), delayed allergy, and abnormal glucose blood level (see Non-patent documents 1 to 3).
Of the side effects as mentioned above, significant recently reported clinical cases involve cardiotoxicity (a heart abnormality inducing lethal arrhythmia which is observed as an abnormality of electrocardiogram with prolonged QT or QTc interval). Some commercially available quinolone antibacterial agents have been reported to produce clearly prolonged QT or QTc interval including some serious cases (abnormality of electrocardiogram inducing lethal arrhythmia) (Non-patent documents 1 to 3). Also reported are side effects such as induction of rash, which is a result of delayed allergy, and abnormal blood glucose level.
Accordingly, in order to enable use the quinolone antibacterial agent as a human or animal drug, there is a demand for a quinolone synthetic antibacterial agent which is provided with an improved safety with weaker side effects such as induction of convulsion associated with concomitant use of a nonsteroidal anti-inflammatory agent, central action, phototoxicity (photosensitivity), and hepatotoxicity, as well as side effects such as cardiotoxicity, delayed allergy, and abnormal glucose blood level. In other words, there is a strong demand for a quinolone compound simultaneously provided with a strong antibacterial activity and selective toxicity.
[Patent Document 1] Japanese Patent Application Laid-Open No. (JP-A) 61-282382
[Patent Document 2] JP-A 63-45261
[Patent Document 3] JP-A 2-231475
[Patent Document 4] JP-A 3-95176
[Non-patent Document 1] Hiroyuki Kobayashi Ed., “Clinical Applications of New-quinolone Agents”, Iyaku-Journal-Sha (2001)
[Non-patent Document 2] Drugs, Vol. 62, No. 1, page 13 (2002)
[Non-patent Document 3] Toxicology Letters, Vol. 127, page 269 (2002)